This invention relates to a novel application of Gibberellins in veterinary and human medicines. In particular the invention concerns pharmaceutical formulations containing Gibberellins and their use for the treatment of diabetes including type 1 and type 2 diabetes and their complications and associated conditions including obesity, micro and macro vascular diseases, nephropathy, neuropathy, eye diseases, diabetic ulcerations and the like.
Gibberellins are a series of naturally occurring compounds, which are known as plant growth regulators with wide application in the plant kingdom [1]. They have also been isolated from metabolites of some microorganisms, such as Gibberella fujikuroi [2]. Gibberellins, especially Gibberellic Acid (Gibberellin A3), and its mixture with Gibberellin A4 and/or Gibberellin A7 which are commercially available, have been extensively applied in agriculture to increase the growth of some fruits (strawberries and grapes) and vegetables (tomatoes, cabbages and cauliflowers), also as food additive in the malting of barley [3].    [1]. J. MacMillian, et al. “Isolation and Structure of Gibberellin From Higher Plants”. Adv. Chem. Ser 28, 18˜24, (1961).    [2].    (a) P. J. Curtis et al. Chem. & Ind. (London) 1066, (1954).    (b) B. E. Cross, J. Chem. Soc. 4670, (1954).    (c) P. W. Brian et al, U.S. Pat. No. 2,842,051.    (d) C. T. Calam et al, U.S. Pat. No. 2,950,288.    (e) A. J. Birch et al, U.S. Pat. No. 2,977,285.    [3].    (a) M. Devlin, Plant Physiology, New York, Reinhold, (1966).    (b) P. W. Brian et al, Plant Physiol, 5,669 (1955).    (c) A. K Mehta et al, J. Hostic Sci 4, 167 (1975).    (d) R. J. Weavor, Adv. Chem. Ser 28, 89 (1961).    (e) F. G. Gustafson, Plant Physical 35, 521 (1960).    (f) Fed. Reg. 25, 2162 (1960).
Gibberellin A3 and its mixture of Gibberellin A4 and/or A7 can be obtained by fermentation of microorganisms such as Gibberella fujikuroi. The crude compounds can be isolated and purified to afford a high purity crystalline product. The other derivatives of Gibberellin can be obtained by either semi-synthetic route from Gibberellin A3 or total synthesis which have been well-documented [4].    [4].    (a) The Merck Index, 12, 4426, literatures cited herein.    (b) Furber M., et al., “New Synthesis Pathways From Gibberellins to Autheridiogens Isolated From the Fern Genus Anemia”, J. of Org. Chem. vol 55, No. 15, 4860˜4870 (1990).    (c) Mander L. N., et al., “C-18 hydroxylation of Gibberellins”, J. C. S., Perkin Trans. 1 (17), 2893˜2894 (2000).    (d) Pour M. et al., “Synthesis of 3,12-Dihydroxy-9,15-Cyclo Gibberellins”, Tetrahedron 54(45), 13833˜13850 (1998).    (e) Liu J. P. et al., “A General Protocol For the Hydroxylation of C-14 in Gibberellins Synthesis of 14-Beta-hydroxy-Gibberellin A1 Methyl Ester”, Tetrahedron 54(38), 11637˜11650 (1998).    (f) Pour M, et al., “Synthetic and Structural Studies on Novel Gibberellins”, Pure and Applied Chemistry 70(2), 351˜354 (1998); “Synthesis of 12-Hydroxy-9,15-Cyclo-Gibberellins”, Tetrahedron Letters, 39(14), 1991˜1994 (1998); Australian J. of Chemistry 50(4), 289˜299 (1997).    (g) King G. R. et al., “A New and Efficient Strategy for the Total Synthesis of Polycyclic Diterpenoids—The Preparation of Gibberellins (+/−)−GA103 and (+/−)−GA73”, J. Am. Chem. Soc. 119(16), 3828˜3829 (1997).    (h) Mander L. N., “Synthesis of 12-Hydroxy-C-20-Giebberellin from Gibberellin A3”, Tetrahedron 53(6), 2137˜2162 (1997) and literatures cited herein.
Furthermore, the extraction and isolation of different Gibberellins from different plants, shoots, fruits and seeds have also been widely published [5].    [5].    (a) Pearce D. W., et al., Phytochemistry, 59(6), 679˜687 (2002).    (b) Chang S. T., et al., Physiologia Plantarum, 112(3), 429˜432 (2001).    (c) Nakayama M. et al., Phytochemistry, 57(5), 749˜758 (2001); 48(4), 587˜593 (1998).    (d) Blake P. S., et al., Phytochemistry, 55(8), 887˜890 (2000); 53(4), 519˜528 (2000).    (e) Koshioka M., et al., J. of the Japanese Society for Horticultural Science, 68(6), 1158˜1160 (1999); 67(6), 866˜871 (1998).    (f) Mander L. N. et al., Phytochemistry, 49(8), 2195˜2206 (1998); 49(6), 1509˜1515(1998).    (g) Wynne G. et al., Phytochemistry, 49(7), 1837˜1840 (1998).
Gibberellins have previously been used for anti-inflammation, treatment of prostatitis and psoriasis, treatment of tumor, and for ulcer and wound healing [6].    [6].    (a) U.S. Pat. No. 4,424,232 January 1984 Parkinson    (b) French 2597339 October 1987    (c) U.S. Pat. No. 5,487,899 January 1996 Davis    (d) U.S. Pat. No. 5,580,857 December 1996 Oden    (e) AUS. 695054 November 1998 Wu    (f) U.S. Pat. No. 6,121,317 September 2000 Wu
We have now found application of Gibberellin or its derivatives for the treatment of diabetes including type 1 and type 2 diabetes and their related conditions.